Readily prepared chiral P,N ligands and their applications in Cu-catalyzed enantioselective conjugate additions

Article abstract of DOI:10.1021/jo0340758

A new type of phosphite-pyridine (P,N) ligand derived from (S)-NOBIN and (S)-BINOL was employed in Cu(I)-catalyzed conjugate addition of diethylzinc to chalcones. The new P,N ligands were highly efficient in the copper-catalyzed enantioselective 1,4-conju

Full text of DOI:10.1021/jo0340758

Rea d ily P r ep a r ed Ch ir a l P ,N Liga n d s a n d
Th eir Ap p lica tion s in Cu -Ca ta lyzed
En a n tioselective Con ju ga te Ad d ition s
Yuanchun Hu, Xinmiao Liang, J unwei Wang,
Zhuo Zheng, and Xinquan Hu*
F IGURE 1. Zhang’s phosphine-pyridine ligand.
SCHEME 1. Syn th esis of P h osp h ite-P yr id in e
Liga n d s 4
Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, Dalian 116023, People’s Republic of China
xinquan@ms.dicp.ac.cn
Received J anuary 22, 2003
Abstr a ct: A new type of phosphite-pyridine (P,N) ligand
derived from (S)-NOBIN and (S)-BINOL was employed in
Cu(I)-catalyzed conjugate addition of diethylzinc to chal-
cones. The new P,N ligands were highly efficient in the
copper-catalyzed enantioselective 1,4-conjugate additions of
diethylzinc to acyclic enones, and up to 97% ee was achieved.
Design and synthesis of chiral ligands play a very
important role in the development of highly enantiose-
lective asymmetric reactions.1 Tunable and easily syn-
thetic ligands are often desired for achieving high enan-
tioselectivities because of strong substrate dependence
in most cases. In fact, subtle changes in conformational,
steric, and/or electronic properties of the chiral ligands
can often lead to dramatic variation of the reactivity and
enantioselectivity. The transition-metal-catalyzed 1,4-
addition of organozinc reagents to conjugate enones is
one of the most important methods of carbon-carbon
bond formation.1,2 In the past decade, great effort has
been made to develop efficient chiral ligands for enanti-
oselective catalytic conjugate additions.3,4 The chiral P,N
ligand-copper complexes have been proven to be efficient
catalysts for 1,4-conjugate addition.5 Among the P,N
ligands, Zhang’s phosphine-pyridine ligand (Figure 1)
showed the best enantioselectivities in the Cu(I)-cata-
lyzed 1,4-conjugate additions of diethylzinc to chalcones;5f
however, the synthetic route was relatively long [six steps
from chiral 2-amino-2′-hydroxy-1,1′-binaphthyl (NOBIN
1,6 Scheme 1)], relatively lower chemical activity was
observed, and electronic and steric properties were
relatively difficult to adjust. We are particularly inter-
ested in exploring some new efficient chiral P,N ligands,
which were easily synthesized and could be finely tuned,
for asymmetric diethylzinc addition to acyclic enones.
Therefore, we have designed and developed a new type
of phosphite-pyridine ligand 4 by tethering a pyridine
amido component and a phosphite component with a
single chiral NOBIN.
Synthesis of the phosphite-pyridine ligands 4 can be
accomplished from NOBIN in two steps (Scheme 1).
Amidation of NOBIN with 2-picolinic acid in the presence
of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpho-
linium chloride (DMTMM)7 as the condensation reagent
proceeded smoothly to afford the amides 2 in high yields.
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; VCH:
Weinheim, Germany, 1999. (b) J acobson, E. N., Pfaltz, A., Yamamoto,
H., Eds. Comprehensive Asymmetric Catalysis I-III; Springer: Berlin,
Germany, 1999. (c) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994.
(2) (a) Hayashi, T.; Tomioka, K.; Yonemitsu, O. Asymmetric
SynthesissGraphical Abstract and Experimental Methods; Kodan-
sha: Tokyo, J apan, 1998. (b) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis; Pergamon: Oxford, U.K., 1992.
(3) For reviews, see: (a) Krause, N.; Roder, A. H. Synthesis 2001,
171. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c) Guiry,
P. J .; McCarthy, M.; Lacey, P. M.; Saunders, C. P.; Kelly, S.; Connolly,
D. J . Curr. Org. Chem. 2000, 4, 821. (d) Feringa, B. L. Acc. Chem.
Res. 2000, 33, 346. (e) Krause, N. Angew. Chem., Int. Ed. Engl. 1998,
37, 283. (f) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 186. (g) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771
and references therein.
(5) For P,N ligands on asymmetric conjugated additions, see: (a)
Shintani, R.; Fu, G. C. Org. Lett. 2002, 4, 3699. (b) Mizutani, H.;
Degrado, S. J .; Hoveyda, A. H. J . Am. Chem. Soc. 2002, 124, 779. (c)
Alexakis, A.; Rosset, S.; Allamand, J .; March, S.; Guillen, F.; Benhaim,
C. Synlett 2001, 1375. (d) Degrado, S. J .; Mizutani, H.; Hoveyda, A.
H. J . Am. Chem. Soc. 2001, 123, 755. (e) Escher, I. H.; Pfaltz, A.
Tetrahedron 2000, 56, 2879. (f) Hu, X.; Chen, H.; Zhang, X. Angew.
Chem., Int. Ed. Engl. 1999, 38, 3518. (g) Knobel, A. K. H.; Escher, I.
H.; Pfaltz, A. Synlett 1997, 1429. (h) Strangeland, E. L.; Sammakia,
T. Tetrahedron 1997, 53, 16503.
(6) For using NOBIN derivatives in asymmetric catalysis, see: (a)
Vsykocil, S.; J aracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek,
M.; Kocovsky, P. J . Org. Chem. 1998, 63, 7738. (b) Vsykocil, S.; J aracz,
S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J .
Org. Chem. 1998, 63, 7727. (c) Singer, R. A.; Carreira, E. M. J . Am.
Chem. Soc. 1995, 117, 12360. (d) Carreira, E. M.; Singer, R. A.; Lee,
W. J . Am. Chem. Soc. 1994, 116, 8837. (e) Carreira, E. M.; Lee, W.;
Singer, R. A. J . Am. Chem. Soc. 1994, 116, 3649.
(4) For some recent research results, see: (a) Liang, L.; Au-Yeung,
T. T.-L.; Chan, A. S. C. Org. Lett. 2002, 4, 3799. (b) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J . Am. Chem. Soc. 2002, 124,
5262. (c) Reetz, M. T.; Gosberg, A.; Moulin, D. Tetrahedron Lett. 2002,
43, 1189. (d) Choi, Y. H.; Choi, J . Y.; Yang, H. Y.; Kim, Y. H.
Tetrahedron: Asymmetry 2002, 13, 801.
(7) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S.
Tetrahedron Lett. 1999, 40, 5327.
10.1021/jo0340758 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
4542
J . Org. Chem. 2003, 68, 4542-4545

TABLE 1. Cu -Ca ta lyzed En a n tioselective 1,4-Con ju ga te Ad d ition of Et 2Zn to Ch a lcon ea
entry
ligand
solvent
T (°C)
Et2Zn/chalcone
yieldb (%)
eec (%)
configd
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
toluene/ClCH2CH2Cl (2/1)
toluene/ClCH2CH2Cl (1/1)
toluene/CH2Cl2 (1/1)
ClCH2CH2Cl
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-10
-10
-10
-10
-10
-10
-20
0
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
35
47
46
52
27
75
63
65
63
62
80
92
15
73
14
85
77
81
26
37
92
91
90
83
75
92
91
54
96
34
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
9
10
20
1/1
1/1
10
11
12
13
14
15
-10
-10
-10
-10
-10
1.2/1
1.5/1
1.5/1
1.5/1
1.5/1
a
b
Reaction was carried out for 12 h in 3 mL of solvent, chalcone (0.5 mmol)/[Cu(CH3CN)4]BF4/ligand 4 ) 1/0.01/0.025. Isolated yield.
c ee values were determined by HPLC with a ChiralPak-AD column. Absolute configuration was assigned by comparison of optical rotation
d
with reported data.
Synthesis of the desired phosphites 4 from 2 could be
done through several methods.8 We prepared optically
pure phosphite-pyridine ligand 4 in high yields (>90%)
by refluxing the mixture of the amide 2 and Feringa’s
phosphorus-amidite 3 in toluene. The advantage of this
method is the convenience of its workup procedure. The
obtained ligands 4 are quite stable in the solid state.
Because the structure of 4 can be easily tuned by
changing the phosphite component or the steric bulk of
R, we can envision that new phosphite-pyridine ligands
could be efficient for copper-catalyzed 1,4-conjugate ad-
ditions.
Chalcone was chosen as a typical substrate to optimize
the reaction conditions for the asymmetric conjugate
addition (Table 1). [Cu(CH3CN)4]BF4 was selected as the
metal precursor for its high performance in the conjugate
addition.5f The conjugate additions of diethylzinc to
chalcone were conducted in the presence of 1 mol % of
[Cu(CH3CN)4]BF4 and 2.5 mol % of ligand 4. The results
summarized in Table 1 showed that pure toluene is
advantageous over halogen-containing solvents or mixed
solvents for achieving high enantioselectivity (entries
1-6). The reaction product was obtained in 92% ee with
toluene as the solvent and 4a as the ligand (entry 6). A
decrease in the reaction temperature from -10 to -20
°C did not give a favorable ee, whereas the enantiose-
lectivity dropped dramatically when the temperature was
increased from -10 to 20 °C (entries 8-10). The reaction
yield was enhanced to 92% when 1.5 equiv of diethylzinc
was used, whereas the ee did not drop (entries 11 and
12 versus entry 6). Replacing ligand (S,S)-4a with its
diastereomer 4b [derived from (R)-NOBIN and (S)-1,1′-
bi-2-naphthol (BINOL)] led to the addition product in a
much lower ee (entry 13 versus entry 12). The result
demonstrated that the two chiral configurations of ligand
(S,S)-4a are matched for the high enantioselectivity of
the reaction. When (S,S)-4c, a more sterically hindered
ligand, was used instead of (S,S)-4a , the reaction product
was obtained in 73% yield and in 96% ee. This enanti-
oselectivity is comparable to the result obtained with the
Cu(I)-phosphine-pyridine system.5f It is noteworthy
that the absolute configuration of the addition product
is dependent on the absolute configuration of the BINOL
moiety of the ligand. To study the influence of the BINOL
moiety of the ligand on the enantioselectivity of the
reaction, structural flexible ligand 4d with an achiral
biphenyl group at the phosphite component was tested
for the reaction. When 4d was employed for the enanti-
oselective conjugate addition, the configuration of the
product was reversed and the obtained ee was only 34%
(entry 15).
We thus used 4c as the ligand for Cu-catalyzed
enantioselective conjugate addition of diethylzinc to
various substituted chalcones (Table 2). The reactions
were carried out at -10 °C in toluene with 1.5 equiv of
diethylzinc as the reagent. As shown in Table 2, excellent
enantioselectivities (up to 97% ee) and yields were
obtained for a variety of substituted chalcones. To our
best knowledge, 97% ee values for chalcone and 4-chlo-
rochalcone (entries 1 and 2) are the best results of copper-
catalyzed conjugate additions to date. For 4′-substituted
chalcones, a major electronic effect was observed. Elec-
tronic-deficient substrates appeared to be beneficial for
the enantioselectivity of the reaction, as >95% ee was
obtained for a 4′-Cl substrate (entry 5), whereas the
result for an electronic-rich substrate was much less
enantioselective (entry 7). In contrast, there was no
electronic effect for 4-substituted chalcones, because all
of the 4-substituted chalcones gave excellent enantiose-
lectivities (entries 2-4). A simple acyclic enone, trans-
4-phenyl-3-buten-2-one, was also used as the substrate
for the conjugate additions (entries 8 and 9). Ligand 4a
(8) (a) Ganapathy, S.; Sekhar, B. B. V. S.; Cairns, S, M.; Akutagawa,
K.; Bentrude, W. G. J . Am. Chem. Soc. 1999, 121, 2085. (b) Reetz, M.
T.; Gosberg, A. Tetrahedron: Asymmetry 1999, 10, 2129. (c) Brunel,
J .-M.; Buono, G. J . Org. Chem. 1993, 58, 7313. (d) Greene, N.; Kee, T.
P. Synth. Commun. 1993, 23, 1651.
J . Org. Chem, Vol. 68, No. 11, 2003 4543

TABLE 2. En a n tioselective 1,4-Con ju ga te Ad d ition of
Et2Zn to Acyclic En on esa
TABLE 3. Asym m etr ic Con ju ga te Ad d ition s of Et 2Zn to
Cyclic En on esa
entry
R1
R2
yieldb (%) eec (%) configd
entry
n
ligand
convb (%)
eeb (%)
configc
1
2
3
4
5
6
7
8
9g
Ph
Ph
Ph
Ph
82
76
86
80
75
71
31
48
64
97
97
97
97
95
89
74
58f
90f
S
e
e
4-Cl-C6H4
+
+
S
-
+
-
S
1
2
3
4
1
1
2
2
4a
4c
4a
4c
90
79
90
33
53
45
31
33
S
S
S
S
4-Me-C6H4
4-MeO-C6H4 Ph
e
e
e
Ph
Ph
Ph
Ph
Ph
4-Cl-C6H4
4-Me-C6H4
4-MeO-C6H4
Me
a
Reaction was carried out at -10 °C for 12 h in 3 mL of toluene
[substrate (1.0 mmol)]/[Cu(CH3CN)4]BF4/ligand 4 ) 1/0.01/0.025.
b
Conversions and ee values were determined by GC with a
Me
S
capillary Gamma-DEX-225 column. c Absolute configuration was
assigned by comparison of optical rotation with reported data.
a
Reaction was carried out at -10 °C for 12 h in 3 mL of toluene
[substrate (1.0 mmol)]/[Cu(CH3CN)4]BF4/ligand 4c ) 1/0.01/0.025.
Isolated yield. c ee values were determined by HPLC with a
b
d
ChiralPak-AD column. Absolute configuration was assigned by
residue was chromatographed on silica gel and eluted with CH2-
comparison of optical rotation with reported data. e Sign of the
optical rotation of addition product. f ee values were determined
Cl2 to afford 1.751 g (90%) of amide 2a as a white solid: mp
202-203 °C; [R]25 -175.5 (c 0.5, CHCl3 ); 1H NMR (DMSO-d6)
D
g
by GC with a capillary Gamma-DEX-225 column. Reaction was
carried out with 4a as the ligand.
δ 6.84 (d, J ) 8.4 Hz, 1H), 7.07 (d, J ) 8.4 Hz, 1H), 7.17-7.32
(m, 3H), 7.43-7.52 (m, 3H), 7.94-8.19 (m, 7H), 8.80-8.83 (m,
1H), 9.95 (s, 1H), 10.04 (s, 1H); 13C NMR (DMSO-d6) δ 112.65,
118.37, 118.49, 119.65, 121.86, 122.13, 122.94, 123.57, 124.78,
125.48, 126.49, 126.86, 127.02, 128.08, 128.30, 130.45, 130.54,
132.73, 133.57, 134.10, 138.32, 148.17, 148.85, 153.30, 153.46,
161.22; HR-MS, calcd for C26H18N2O2 390.1368, found 390.1362.
(R)-(+)-2-(2-P yr id in ylca r boxa m id o)-2′-h yd r oxyl-1,1′-bi-
n a p h th yl (2b). The amide 2b (1.845 g, 95%) was prepared from
0.738 g of picolinic acid (6.0 mmol) and 1.428 g of (R)-NOBIN
(5.0 mmol) according to the same procedure as used for 2a and
afforded a 90% ee for the addition product, which was
much better than that obtained from 4c.
To extend the range of substrates for these catalysts,
the conjugate additions of Et2Zn to cyclic enones were
also examined (Table 3); however, ligands 4a and 4c did
not show their enantioselectivities like the reaction of
chalcones. These results showed that the new P,N
ligand-copper complexes were not proper catalysts for
conjugate additions of cyclic enones.
In summary, a new type of phosphite-pyridine ligand
4 derived from (S)-NOBIN and (S)-BINOL has been
developed. Ligand 4c has been successfully applied in Cu-
catalyzed conjugate addition of Et2Zn to chalcones, and
up to 97% ee has been obtained. Less sterically hindered
ligand 4a showed good results, up to 90% ee, for trans-
4-phenyl-3-buten-2-one as the substrate. Further study
will be focused on the applications of the new P,N ligands
4 in other asymmetric catalytic reactions and progress
will be reported in due course.
isolated as a white solid: mp 202-203 °C; [R]25 +174.5 (c 0.5,
D
CHCl3); 1H NMR (DMSO-d6) δ 6.85 (d, J ) 8.4 Hz, 1H), 7.08 (d,
J ) 8.4 Hz, 1H) 7.18-7.32 (m, 3H), 7.43-7.53 (m, 3H), 7.94-
8.19 (m, 7H), 8.82 (d, J ) 9.2 Hz, 1H), 9.97 (s, 1H), 10.05 (s,
1H); 13C NMR (DMSO-d6) δ 112.68, 118.40, 118.52, 119.68,
121.88, 122.16, 122.95, 123.59, 124.80, 125.50, 126.50, 126.87,
127.02, 128.10, 128.32, 130.47, 130.56, 132.76, 133.59, 134.14,
138.31, 148.17, 148.87, 153.33, 153.49, 161.24; HR-MS, calcd for
C26H18N2O2 390.1368, found 390.1374.
(S)-(-)-2-(6-Meth yl-2-pyr idin ylcar boxam ido)-2′-h ydr oxyl-
1,1′-bin a p h th yl (2c). The amide 2c (1.714 g, 85%) was prepared
from 0.826 g of 6-methylpicolinic acid (6.0 mmol) and 1.428 g of
(S)-NOBIN (5.0 mmol) according to the same procedure as used
for 2a and isolated as a white solid: mp 272-274 °C; [R]25
D
1
-190.5 (c 0.5, CHCl3); H NMR (DMSO-d6) δ 2.07 (s, 3H), 6.87
(d, J ) 8.0 Hz, 1H), 7.15-7.54 (m, 7H), 7.78-8.15 (m, 6H), 8.93
(d, J ) 9.2 Hz, 1H), 9.90 (s, 1H), 10.31 (s, 1H); 13C NMR (DMSO-
d6) δ 23.22, 112.70, 118.52, 118.67, 121.41, 122.96, 123.48,
124.63, 125.43, 126.40, 126.52, 126.93, 128.10, 128.29, 128.48,
130.42, 132.78, 133.60, 134.14, 134.22, 138.35, 148.02, 153.45,
153.60, 156.64, 160.98; HR-MS, calcd for C27H20N2O2 404.1525,
found 404.1542.
Exp er im en ta l Section
Gen er a l. All reactions were carried out in an argon atom-
sphere using standard Schelenk techniques. All solvents were
dried before use according to standard procedures and stored
under argon. Feringa’s phosphorus amidite 3 was prepared
according to a literature procedure.9
Syn th esis of th e Liga n d s: (S,S)-(+)-4a . Typ ica l P r oce-
d u r e. Amide 2a (390.4 mg, 1.0 mmol), 467.2 mg of (S)-Feringa’s
phosphorus-amidite ligand 3 (1.3 mmol), and 15 mL of toluene
were added to a 50 mL air-free Schlenk flask with a reflux
condenser under an argon atmosphere. The mixture was heated
to reflux; initially the mixture turned into a colorless solution,
and then precipitation occurred in a few hours. After 24 h of
refluxing, the reaction mixture was cooled to room temperature.
The resulting white solid was collected by filtration under argon,
washed with toluene (2 × 2 mL), and dried in vacuo to afford
667.2 mg of ligand 4a (95%) as a white solid: mp 292-294 °C;
Syn th ess of Am ides: (S)-(-)-2-(2-P yr idin ylcar boxam ido)-
2′-h yd r oxyl-1,1′-bin a p h th yl (2a ). Typ ica l P r oced u r e. A
mixture of 0.740 g of picolinic acid (6.0 mmol) and 1.428 g of
(S)-NOBIN (5.0 mmol) in 25 mL of THF was stirred at room
temperature for 10 min; 1.522 g of condensation agent DMTMM
(5.5 mmol) was added to the mixture and stirred at room
temperature. After the reaction was complete (detected by TLC),
20 mL of water was added into the reaction mixture. Separated
layers and aqueous layer were extracted with diethyl ether (3
× 20 mL). The combined organic layers were successively
washed with 5 mL of saturated sodium bicarbonate, brine, and
5% of HCl and brine and then dried over anhydrous Na2SO4.
The solvent was concentrated under reduced pressure. The
[R]25 174.9 (c 0.5, THF); 1H NMR (DMSO-d6) δ 6.72 (d, J ) 8.8
D
Hz, 1H), 7.00-7.10 (m, 4H), 7.30-7.47 (m, 10H), 7.79 (d, J )
9.2 Hz, 1H), 7.86-8.18 (m, 9H), 8.30-8.36 (m, 2H), 8.88-8.92
(m, 1H), 9.86 (s, 1H); 13C NMR (DMSO-d6) δ 121.16, 124.66,
125.04, 125.37, 125.62, 125.86, 126.37, 126.62, 126.76, 126.90,
127.71, 128.21, 128.54, 129.39, 129.77, 130.71, 131.31, 138.02,
(9) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron: Asymmetry
1994, 5, 699.
4544 J . Org. Chem., Vol. 68, No. 11, 2003

147.87; 31P NMR δ +144.86; HR-MS, calcd for C46H29N2O4P
704.1865, found 704.1857.
121.54, 121.66, 124.53, 125.02, 125.53, 126.90, 127.71, 128.11,
128.51, 129.08, 129.19, 129.45, 129.60, 129.95, 130.36, 130.92,
131.34, 132.61, 132.71, 134.65, 138.11, 147.64, 147.83, 148.31,
160.94; 31P NMR (DMSO-d6) δ +148.89; HR-MS, calcd for
(S,R)-(+)-4b. Ligand 4b (663.8 mg, 94%) was prepared from
390.4 mg of amide 2b (1.0 mmol) and 466.3 mg of 3 (1.3 mmol)
according to the same procedure as used for 4a and isolated as
a white solid: mp 220-222 °C; [R]25D 116.1 (c 0.5, THF); 1H NMR
(DMSO-d6) δ 6.21 (d, J ) 8.8 Hz, 1H), 7.04-7.15 (m, 4H), 7.25-
7.59 (m, 11H), 7.75 (d, J ) 8.8 Hz, 1H), 7.90-8.37 (m, 10H),
8.94 (d, J ) 8.8 Hz, 1H), 9.97 (s, 1H); 13C NMR (DMSO-d6) δ
119.59, 119.95, 121.12, 121.26, 121.67, 121.82, 124.66, 125.24,
125.49, 125.75, 125.82, 125.89, 126.57, 126.81, 127.11, 127.95,
128.36, 128.43, 128.65, 129.54, 129.71, 130.60, 130.88, 131.11,
131.18, 131.40, 131.58, 131.81, 132.82, 134.81, 138.33, 146.05,
146.56, 147.85, 148.03, 148.44, 161.15; 31P NMR δ +144.83; HR-
MS, calcd for C46H29N2O4P 704.1865, found 704.1852.
(S,S)-(+)-4c. Ligand 4c (686.7 mg, 96%) was prepared from
404.3 mg of amide 2c (1.0 mmol) and 466.2 mg of 3 (1.3 mmol)
according to the same procedure as used for 4a and isolated as
a white solid: mp 273-275 °C; [R]25D 164.7 (c 0.5, THF); 1H NMR
(CDCl3) δ 1.90 (s, 3H), 6.38 (d, J ) 8.4 Hz, 1H), 6.92 (d, J ) 7.6
Hz, 1H), 7.11-7.50 (m, 14H), 7.63 (d, J ) 8.4 Hz, 2H), 7.75-
8.16 (m, 8H), 9.13 (d, J ) 8.8 Hz, 1H), 10.20 (s, 1H); 13C NMR
(CDCl3) δ 23.68, 118.72, 119.36, 119.92, 121.43, 121.51, 121.68,
121.74, 122.44, 124.30, 124.79, 124.94, 125.14, 125.61, 125.87,
126.27, 126.79, 126.84, 127.04, 127.57, 128.21, 128.31, 128.41,
129.67, 130.25, 130.75, 130.82, 131.16, 131.45, 131.54, 132.25,
132.77, 133.45, 133.81, 135.52, 137.29, 146.96, 147.38, 148.42,
148.49, 148.66, 156.47, 161.90; 31P NMR δ +146.61; HR-MS,
calcd for C47H31N2O4P 718.2021, found 718.2050.
C
38H25N2O4P 604.1552, found 604.1560.
Gen er a l P r oced u r e for Asym m etr ic 1,4-Con ju ga te Ad -
d ition : P r ep a r a tion of Ca ta lyst. 4c (71.8 mg, 0.10 mmol),
12.6 mg of [Cu(CH3CN)4]BF4 (0.04 mmol), and 10 mL of toluene
were added to a 50 mL air-free Schlenk flask under an argon
atmosphere. After 30 min of stirring at room temperature, the
solvent was stripped off in vacuo, 6 mL of CH2Cl2 was added to
the flask, and the catalyst solution was used for four separate
conjugate addition reactions.
Asym m etr ic 1,4-Con ju ga te Ad d ition . Chalcone substrate
(1 mmol) and 1.5 mL of the above prepared catalyst solution
were added to a flame-dried Schlenk tube under an argon
atmosphere. After the solvent had been stripped off, 3 mL of
toluene was added. The slurry was stirred at room temperture
for 10 min and then cooled to the desired temperature. After
the slurry had been stirred for 15 min, 1.4 mL of Et2Zn (1.1 M
in toluene, 1.5 mol equiv) was added slowly. The resulting
mixture was stirred at that temperature for 12 h. Four milliliters
of 5% hydrochloric acid was added to quench the reaction. The
mixture was allowed to warm to room temperature, and then
15 mL of diethyl ether was added. The organic layer was washed
with 5 mL of saturated NaHCO3 and 5 mL of brine and then
dried over anhydrous Na2SO4. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatagraphy on silica gel and eluted with EtOAc/hexanes
(1/40-1/20) to afford the addition product. The ee values of the
addition products were determined by chiral HPLC or capillary
GC. The analytical conditions are given in the Supporting
Information.
(S)-(-)-4d . 2,2′-Biphenol (286 mg, 1.0 mmol), 163 mg of
hexamethylphosphorustriamide (1.0 mmol), 2.0 mg of NH4Cl,
and 5 mL of toluene were added to a 25 mL air-free Schlenk
flask equipped with a reflux condenser under argon atmosphere.
The mixture was heated to 90 °C for 12 h, and then the reaction
mixture was filtered to remove NH4Cl. The filtrate, 5 mL of
toluene, and 195.2 mg of (S)-2a (0.5 mmol) were added to a new
dried 50 mL Schlenk flask under an argon atmosphere. The
mixture was heated to reflux. After 15 h of stirring, the reation
solution was cooled to room temperature and purified by flash
chromatograghy on silica gel and eluted with CH2Cl2 to afford
241.3 mg (80%) of (S)-4d as a white foamy solid: mp 79-82 °C;
Ack n ow led gm en t. This work was supported by the
National Science Foundation of China (29933050) and
the Young Faculty Research Fund of DICP.
Su p p or tin g In for m a tion Ava ila ble: ee value determi-
nation conditions of HPLC and GC, spectra of 2a -c, 4a -d
(1H NMR, 13C NMR, and 31P NMR). This material is available
free of charge via the Internet at http://pubs.acs.org.
[R]15 -6.7 (c 1.2, THF); 1H NMR (DMSO-d6) δ 6.58 (d, J ) 7.6
D
Hz, 1H), 6.73 (d, J ) 7.2 Hz, 1H), 7.05-7.54 (m, 13H), 7.77 (d,
J ) 8.8 Hz, 1H), 7.89-8.37 (m, 7H), 8.95 (d, J ) 9.2 Hz, 1H),
9.96 (S, 1H); 13C NMR (DMSO-d6) δ 119.36, 119.77, 121.25,
J O0340758
J . Org. Chem, Vol. 68, No. 11, 2003 4545